Our long-term objectives are to elucidate peripheral receptors on nociceptors that can be targeted to control pain. We are focusing on metabotropic glutamate receptors (mGluRs), Group II mGluRs in particular, because they produce inhibition and long term neuronal depression in the CNS. If Group I1activation produces the same inhibitory modulation in the periphery, selective activation of Group II mGluRs on nociceptors may provide powerful and long lasting depression of noxious input. Our central hypothesis is that Group II mGluRs are integral components of peripheral sensory integration. Specifically, we hypothesize that the anti-hyperalgesic effect of Group II mGluR activation is achieved by inhibition of capsaicin (VR1) and ATP (P2X3) receptors and by a reduction in excitatory glutamate-induced activation and glutamate release from primary afferent fibers and a decrease in neurogenic inflammation. We will co-localize VR1 and P2X3 receptors with Group II mGluRs in dorsal root ganglion (DRG) cells, demonstrating that these receptor populations are present and can interact within the same DRG cell (specific aim 1). Physiological studies using an in vitro skin-nerve preparation and behavioral studies will confirm the presence of Group II mGluRs on nociceptors and demonstrate that their activation does not effect normal nociception but reduces nociceptor sensitization and nociceptive behaviors induced by capsaicin, ATP or glutamate (specific aims 2,3). Microdialysis studies in the hindpaw will show that Group II mGluR activation can reduce glutamate release (specific aim 4). Activation of peripheral Group II mGluRs will reduce signs of neurogenic inflammation (specific aim 5). Finally, in Specific aim 6 will we show that Group I! mGluRs and VR1 receptors are functionally linked through a cAMPIPKA pathway. The data suggest that inhibitory Group II mGluRs play a major role in the modulation of inflammatory pain and so are likely targets for the development of peripherally acting therapeutics for pain control. There is obvious value for human health if our hypotheses are borne out. Targeting a peripheral receptor population selectively to produce multiple antihyperalgesic effects is highly desirable for an analgesic compound. Enhancing activity of peripheral inhibitory Group II mGluRs could provide a non-opioid therapy for pain, avoiding CNS and PNS side effects inherent in opioid treatment. [unreadable] [unreadable] [unreadable]